The objective of this research program is to use protein engineering to generate staphylococcal Protein A variant which possess strong binding affinity for immunoglobulin species which are not significantly bound by natural Protein A. The experimental program will involve a sequential series of experiments of increasing levels of difficulty encompassing structural design, variant construction and testing of immunoglobulin binding. Based on the existing Protein A/immunoglobulin Fc cocrystal structure, computer modeling and genetic engineering technologies will be used to design and produce Protein A variants with high engineered affinity for (1) human IgG3; (2) mouse IgG1: and, (3) human IgM for the clinical diagnostics and therapeutics market. If successful, this modification of the binding specificity of a protein-protein complex will be a milestone in the development of protein engineering and will also serve as a preface to the engineering of Protein A variant that bind other immunoglobulin classes, e.g., IgE, IgD, and IgA. The engineered affinity protein for human IgM will have utility as a diagnostic reagent for antigen-specific IgM, and as a therapeutic in extracorporeal blood filtration for diseases including cancer and AIDS.